Hepatitis B virus (HBV)
infection remains one of the most serious health problems worldwide. Whilst studies have shown that HBV impairs
interferon (IFN) production from dendritic cells in
chronic hepatitis B patients, it remains unknown whether HBV inhibits IFN production in human hepatocytes. Using transient transfection assays in a primary human hepatocyte cell line (PH5CH8), this study demonstrated that
HBV polymerase inhibits IFN-beta promoter activity induced by Newcastle disease virus, Sendai virus or
poly(I : C) in a dose-dependent manner, whilst ectopic expression of the HBV core and X
proteins had no effect on IFN-beta promoter activity. In addition,
HBV polymerase blocked cellular IFN-beta expression and consequent
antiviral immunity revealed by an
infection protection assay. Furthermore, overexpression of key molecules on the IFN-beta induction axis, together with
HBV polymerase, resulted in a block of IFN-beta promoter activity triggered by RIG-I, IPS-1, TRIF, TBK1 and
IKKepsilon, but not by an
IFN regulatory factor 3 dominant-positive mutant (IRF3-5D), suggesting that
HBV polymerase prevents IFN-beta expression at the TBK1/
IKKepsilon level. Further studies showed that
HBV polymerase inhibited phosphorylation, dimerization and nuclear translocation of IRF3, in response to Sendai virus
infection. Finally, it was shown that
HBV polymerase-mediated dampening of the interaction between TBK1/
IKKepsilon and DDX3 may be involved in the inhibitory effect on IFN-beta induction. Taken together, these findings reveal a novel role of
HBV polymerase in HBV counteraction of IFN-beta production in human hepatocytes.